Effects of Leishmania infantum infection on DNA methylation in human neutrophils

• Grant number: 18/26564-1
• Support Opportunities: Regular Research Grants
• Start date: December 01, 2019
• End date: November 30, 2022
• Field of knowledge: Biological Sciences - Immunology - Immunogenetics
• Principal Investigator: Flavia Lombardi Lopes
• Grantee: Flavia Lombardi Lopes
• Host Institution: Faculdade de Medicina Veterinária (FMVA). Universidade Estadual Paulista (UNESP). Campus de Araçatuba. Araçatuba , SP, Brazil
• Associated researchers: Valéria Marçal Felix de Lima

Abstract

Leishmaniasis is an endemic disease, common in poor regions of developing countries. It is a parasitic disease responsible for the second-highest mortality rate, and in its visceral form, when caused by the protozoan Leishmania (Leishmania) infantum (syn. Chagasi), it can be fatal if left untreated. Common symptoms include fever, anorexia, weight loss, abdominal distension, and weakness, in addition to the classic clinical manifestations of spleen and hepatomegaly. Approximately 350 million people live in susceptible areas, and between 2001 and 2017, only in the state of São Paulo, 3,472 cases were reported. Among the vertebrate hosts, there is a great variety of mammals, and the transmission occurs mainly through airborne vectors: females of sandflies of the genus Lutzomyia. The innate immune response is crucial in the initial phase of infection, neutrophils being the first recruited cells, followed by macrophages. The parasites use the neutrophils as safe and transient shelter, later invading the macrophages, where they are able to replicate. Two different types of an adaptive immune response, the classical activation (Th1) or the alternative pathway (Th2) can be activated soon after, favoring the survival of the pathogen. The immune response is intensely regulated by epigenetic processes, thus ensuring a time-tissue regulation. Epigenetic changes are dynamic, being able to act concomitantly or separately, developing an essential role in immune modulation. DNA methylation interferes with gene expression through two mechanisms, in the direct mechanism, through a physical barrier; and in the indirect, acts by recruiting co-repressor proteins and histone deacetylases, which condense the DNA, causing gene silencing. Considering the importance of methylation during physiological and pathological processes and the high rates of mortality and morbidity of leishmaniasis due to ineffective treatment, the present study aims to elucidate the host/microorganism dialogue in the epigenetic control of human neutrophil response to L. (L.) infantum (syn. chagasi), as well as to associate possible alterations in the epigenetic patterns with the control of gene expression of this cellular type in an in vitro infection model. (AU)